1. The role of EMEA in Orphan Drug Development Thomas Lönngren, EMEA Stockholm, 15 February 2005

2. 15 Feb 2005 – Thomas Lönngren Slide: 2 European Medicines Agency www.emea.eu.int The European Medicines Agency EMEA is the European Union body responsible for the evaluation and supervision of medicines in Europe. Its main responsibility is the protection and promotion of public and animal health. The EMEA works as a network, bringing together the scientific resources of the Member States. The Agency cooperates closely with international partners on a wide range of regulatory issues (e.g. ICH, WHO, FDA, etc) The Agency was created in 1995 and is headquartered in London.

3. 15 Feb 2005 – Thomas Lönngren Slide: 3 European Medicines Agency www.emea.eu.int Drug Therapy in Rare Diseases Persons suffering from rare diseases have the same rights as their fellow citizens to safe and effective therapies

4. 15 Feb 2005 – Thomas Lönngren Slide: 4 European Medicines Agency www.emea.eu.int Orphan Regulations Regulation (EC) No 141/2000 of the European Parliament and of the Council on Orphan Medicinal Products of 16 December 1999 Commission Regulation (EC) No 847/2000 of 27 April 2000

5. 15 Feb 2005 – Thomas Lönngren Slide: 5 European Medicines Agency www.emea.eu.int What is an Orphan Medicinal Product Orphan Medicinal Products for rare diseases (affecting less than 5 in 10,000 persons) development costs > expected return on investment life-threatening or very serious Lack of sponsors developing orphan medicinal products

6. 15 Feb 2005 – Thomas Lönngren Slide: 6 European Medicines Agency www.emea.eu.int What are the EU incentives ? Protocol Assistance free scientific advice to optimise development EU-Funded Research grants from Community & Member State programmes Fee Reductions reduction of centralised regulatory fees via a special fund from EU budgetary authority Market Exclusivity for 10 years after grant of EU marketing authorisation Centralised Procedure direct access to EMEA centralised procedure for marketing authorisation

7. 15 Feb 2005 – Thomas Lönngren Slide: 7 European Medicines Agency www.emea.eu.int Application for Orphan Designation Application should demonstrate orphan criteria have been met: life-threatening or debilitating nature of condition medical plausibility prevalence < 5 in 10,000 or unlikely to generate sufficient return on investment no satisfactory methods exist or medicinal product will be of significant benefit All claims should be substantiated by references

8. 15 Feb 2005 – Thomas Lönngren Slide: 8 European Medicines Agency www.emea.eu.int Committee for Orphan Medicinal Products (COMP) EMEA Committee: 31 members + Chairman 1 Member per Member State 3 representatives from patients groups 3 members proposed by the EMEA COMP responsible for: opinions on designation advising on general EU policies international co-operation

9. 15 Feb 2005 – Thomas Lönngren Slide: 9 European Medicines Agency www.emea.eu.int Procedure for Orphan Designation Evaluation Opinion Decision- Making Designation Validation Day 1 Day 90 + 30 days Pre- submission

10. 15 Feb 2005 – Thomas Lönngren Slide: 10 European Medicines Agency www.emea.eu.int Status of Orphan Applications Up to January 2005

11. 15 Feb 2005 – Thomas Lönngren Slide: 11 European Medicines Agency www.emea.eu.int Distribution of opinions Up to December 2004

12. 15 Feb 2005 – Thomas Lönngren Slide: 12 European Medicines Agency www.emea.eu.int Opinions designated based on significant benefit Up to January 2005: 182 out of 262 opinions (69%) based on assumption of significant benefit over authorised treatments in the orphan condition Significant benefit to be reviewed at the time of Marketing Authorisation to maintain orphan status

13. 15 Feb 2005 – Thomas Lönngren Slide: 13 European Medicines Agency www.emea.eu.int Protocol Assistance Article 6 of Regulation (EC) No 141/2000 Protocol Assistance = Scientific Advice for companies developing Orphan Medicinal Products Revised procedure adopted by the CHMP 2003 Implementation of changes from new Pharmaceutical Regulation by end 2005

14. 15 Feb 2005 – Thomas Lönngren Slide: 14 European Medicines Agency www.emea.eu.int Protocol Assistance – Key Features Systematic pre-submission meeting with the EMEA Oral explanations in the majority of cases Additional and specific expertise to participate in SAWP Involvement of 2 representatives of the Committee for Orphan Medicinal Products in SAWP (Significant Benefit issues) Fee reduction (currently 100% = free)

15. 15 Feb 2005 – Thomas Lönngren Slide: 15 European Medicines Agency www.emea.eu.int Scientific Advice / Protocol Assistance Procedures

16. 15 Feb 2005 – Thomas Lönngren Slide: 16 European Medicines Agency www.emea.eu.int Orphan Medicinal Products Application for Marketing Authorisation (MAA) At the stage of MAA: Filing can currently be through Mutual Recognition Procedure or Centralised Procedure To obtain Market Exclusivity MA must be granted by all Member States in Mutual Recognition In November 2005, Centralised filing obligatory Fee reductions are granted by some MS’s and by EMEA for centralised applications

17. 15 Feb 2005 – Thomas Lönngren Slide: 17 European Medicines Agency www.emea.eu.int Status of Orphan Marketing Authorisation Applications 18 authorisations granted to date Fabrazyme for Fabry disease Replagal for Fabry disease Glivec for chronic myeloid leukaemia Tracleer for pulmonary arterial hypertension Trisenox for acute promyelocytic leukaemia Somavert for acromegaly Zavesca for Gaucher disease Carbaglu for hyperammonaemia

18. 15 Feb 2005 – Thomas Lönngren Slide: 18 European Medicines Agency www.emea.eu.int Status of Orphan Marketing Authorisation Applications cont’d Aldurazyme for Mucopolysaccharidosis Busilvex for haematopoietic progenitor cell transplantation Ventavis for pulmonary arterial hypertension Onsenal for Familial Adenomatous Polyposis Litak for Hairy cell leukaemia Lysodren for adrenal cortical carcinoma Pedea for Patent Ductus Arteriosus Photobarr for Barret’s oesophagus Wilzin for Wilson's disease Xagrid for Thrombocythaemia

19. 15 Feb 2005 – Thomas Lönngren Slide: 19 European Medicines Agency www.emea.eu.int Status of Orphan Marketing Authorisation Applications cont’d Two CHMP Opinions in decision-making Orfadin for Hereditary tyrosinemia type 1 Prialt for chronic pain Three extensions of indication Glivec for Gastrointestinal Stromal Tumours Glivec for first line use in Chronic Myeloid Leukaemia Glivec for paediatric use in Chronic Myeloid Leukaemia Nine centralised applications in review process Four applications filed through Mutual Recognition

20. 15 Feb 2005 – Thomas Lönngren Slide: 20 European Medicines Agency www.emea.eu.int Overview of “evidence” in authorised products Data provided –in 28% of products phase III studies (double blind, randomised, placebo controlled) –in 44% of products phase II studies 61% of Marketing Authorisations granted under “exceptional circumstances”

21. 15 Feb 2005 – Thomas Lönngren Slide: 21 European Medicines Agency www.emea.eu.int Orphan Marketing Authorisations 240 designated 45 marketing applic’ns 19 authorised 830,000 patients